This Project will test the hypothesis that activation of NFkB in microglia, and in cells that constitute the blood-brain barrier (BBB), may contribute to the neuropathogenesis of AIDS, and the blockade of NFkB may have therapeutic potential in this setting. The following Specific Aims are proposed. (1) Examine whether persistent NFkB activation is correlated with the release of neurotoxins from, or HIV-1 replication in, microglia. Experiments will also be conducted to test directly whether NFkB activation leads to production of neurotoxins by microglia, and whether specific blockade of NFkB leads to inhibition of the release of neurotoxins from, or HIV-1 replication 1, microglia. (2) Employ cell culture models for the BBB (brain microvascular endothelial cells [BMVECs] and astrocytes) to test the hypothesis that activation of NFkB in cells that comprise the BBB may result in damage to the integrity of this barrier. Experiments will determine whether NFkB activation leads to increased expression of adhesion molecules or metallo-proteases by MBVECs and astrocytes, and studies will also be conducted to test whether induction of these proteins by TNF-alpha is prevented by specific blockade of NFkB. In addition, analogous experiments will be conducted using in vitro assays for BBB integrity. Specifically, the integrity of MMVEC and BMVEC/astrocyte monolayers will be assessed by measuring their permeability to macromolecules and by quantitating trans-monolayer migration by monocytes. (3) Test broadly-based anti-oxidant and anti- inflammatory drugs for their ability to block NFkB activation in microglia and in BMVECs. Data from these studies will be correlated with effects on neurotoxin release (microglia) and adhesion molecule and metalloprotease expression (BMVECs). Taken together, these experiments are expected to result in the identification of novel therapeutic strategies for the treatment of HIV-1 dementia.